title: Synaptic dysbindin-1 reductions in schizophrenia occur in an isoform-specific manner indicating their subsynaptic location.
abstract: BACKGROUND
  An increasing number of studies report associations between variation in DTNBP1, a top candidate gene in schizophrenia, and both the clinical symptoms of the disorder and its cognitive deficits. DTNBP1 encodes dysbindin-1, reduced levels of which have been found in synaptic fields of schizophrenia cases. This study determined whether such synaptic reductions are isoform-specific.
  
  
  RESULTS
  Using Western blotting of tissue fractions, we first determined the synaptic localization of the three major dysbindin-1 isoforms (A, B, and C). All three were concentrated in synaptosomes of multiple brain areas, including auditory association cortices in the posterior half of the superior temporal gyrus (pSTG) and the hippocampal formation (HF). Tests on the subsynaptic tissue fractions revealed that each isoform is predominantly, if not exclusively, associated with synaptic vesicles (dysbindin-1B) or with postsynaptic densities (dysbindin-1A and -1C). Using Western blotting on pSTG (n = 15) and HF (n = 15) synaptosomal fractions from schizophrenia cases and their matched controls, we discovered that synaptic dysbindin-1 is reduced in an isoform-specific manner in schizophrenia without changes in levels of synaptophysin or PSD-95. In pSTG, about 92% of the schizophrenia cases displayed synaptic dysbindin-1A reductions averaging 48% (p = 0.0007) without alterations in other dysbindin-1 isoforms. In the HF, by contrast, schizophrenia cases displayed normal levels of synaptic dysbindin-1A, but 67% showed synaptic reductions in dysbindin-1B averaging 33% (p = 0.0256), while 80% showed synaptic reductions in dysbindin-1C averaging 35% (p = 0.0171).
  
  
  CONCLUSIONS
  Given the distinctive subsynaptic localization of dysbindin-1A, -1B, and -1C across brain regions, the observed pSTG reductions in dysbindin-1A are postsynaptic and may promote dendritic spine loss with consequent disruption of auditory information processing, while the noted HF reductions in dysbindin-1B and -1C are both presynaptic and postsynaptic and could promote deficits in spatial working memory.
authors.affiliation: Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. talbotk2@mail.med.upenn.edu
authors.forename: Konrad
authors.initials: K
authors.lastname: Talbot
authors.forename: Natalia
authors.initials: N
authors.lastname: Louneva
authors.forename: Julia W
authors.initials: JW
authors.lastname: Cohen
authors.forename: Hala
authors.initials: H
authors.lastname: Kazi
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Blake
authors.forename: Steven E
authors.initials: SE
authors.lastname: Arnold
mesh_terms: D000368:Aged; D000818:Animals; D000915:Antibody Affinity; D001344:Autopsy; D002352:Carrier Proteins / Q000378:metabolism*; D016022:Case-Control Studies; D003710:Demography; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D020033:Protein Isoforms / Q000378:metabolism; D012559:Schizophrenia / Q000378:metabolism* / Q000473:pathology; D013347:Subcellular Fractions / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D013574:Synaptosomes / Q000378:metabolism; D013702:Temporal Lobe / Q000378:metabolism / Q000473:pathology
chemical_list: D002352:Carrier Proteins; C432416:DTNBP1 protein, human; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D020033:Protein Isoforms